Recurrent tendosynovitis as a rare manifestation of a lipid disorder.

A 33-year-old female had suffered from spontaneously recurrent bursitis and tendosynovitis/enthesitis of the patellar and Achilles tendons for about 10 years. The episodes of immobilization increased. Ultrasound imaging of the swollen and painful tendons showed chronic inflammation with neoangiogenesis within the tendons and hypoechoic lesions. Clinical and laboratory tests did not provide evidence for a rheumatic disease. Low density lipoprotein cholesterol was elevated. Biopsies of skin lesions did not confirm the suspicion of cutaneous xanthomas. Genetic testing for familial hypercholesterolemia was negative. Campesterol and sitosterol were elevated 7- to 12-fold and 20- to 38-fold over the upper limit of normal on two occasions. There was no relevant mutation in ABCG5. In ABCG8, we identified a missense mutation c.1267G>A in exon 9 changing glutamic acid 423 into lysine within the transmembrane domain, and an insertion of adenine (c.1487insA) leading to a frameshift and a premature stop codon (Ile497Aspfs*105). The patient had no clinical evidence of premature atherosclerosis. Therapeutic approaches with nonsteroidal antirheumatic drugs, prednisone, statins, and ezetimibe accompanied by a diet poor in plant sterols led to a relief of symptoms. This case report shows that tendon xanthoma along with tendosynovitis, especially on extensor areas, is suspicious for hypercholesterolemia as the underlying cause. The absence of atherosclerotic plaques in the abdominal aorta and in the carotid arteries on ultrasound may suggest that phytosterolemia is not necessarily accompanied by premature vascular disease.

WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects.

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature. The Seattle International Registry recruits patients from all over the world to investigate genetic causes of a wide variety of progeroid syndromes in order to contribute to the knowledge of basic mechanisms of human aging. Given the unusually high prevalence of WS patients and heterozygous carriers in Japan, the major goal of the Japanese Consortium is to develop effective therapies and to establish management guidelines for WS patients in Japan and elsewhere. This review will also discuss potential translational approaches to this disorder, including those currently under investigation.

Combined immunodeficiency develops with age in Immunodeficiency-centromeric instability-facial anomalies syndrome 2 (ICF2).

The autosomal recessive immunodeficiency-centromeric instability-facial anomalies syndrome (ICF) is characterized by immunodeficiency, developmental delay, and facial anomalies. ICF2, caused by biallelic ZBTB24 gene mutations, is acknowledged primarily as an isolated B-cell defect. Here, we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course as well as putative autoimmune phenomena such as granulomatous hepatitis and nephritis. We also demonstrate impaired cell-proliferation and increased cell death of immune and non-immune cells as well as data suggesting a chromosome separation defect in addition to the known chromosome condensation defect.

Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness.

OBJECTIVE: To identify the cause of a so-far unreported phenotype of infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). METHODS: We characterized a consanguineous family of Yazidian-Turkish descent with IMNEPD. The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. We performed whole-exome sequencing followed by bioinformatic analysis and Sanger sequencing on affected and unaffected family members. The effect of mutations in the candidate gene was studied in wild-type and mutant mice and in patient and control fibroblasts. RESULTS: In a consanguineous family with two individuals with IMNEPD, we identified a homozygous frameshift mutation in the previously not disease-associated peptidyl-tRNA hydrolase 2 (PTRH2) gene. PTRH2 encodes a primarily mitochondrial protein involved in integrin-mediated cell survival and apoptosis signaling. We show that PTRH2 is highly expressed in the developing brain and is a key determinant in maintaining cell survival during human tissue development. Moreover, we link PTRH2 to the mTOR pathway and thus the control of cell size. The pathology suggested by the human phenotype and neuroimaging studies is supported by analysis of mutant mice and patient fibroblasts. INTERPRETATION: We report a novel disease phenotype, show that the genetic cause is a homozygous mutation in the PTRH2 gene, and demonstrate functional effects in mouse and human tissues. Mutations in PTRH2 should be considered in patients with undiagnosed multisystem neurologic, endocrine, and pancreatic disease.

Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer families.

RAD51C was defined by Meindl et al. in 2010 as a high-risk gene involved in hereditary breast and ovarian cancers. Although this role seems to be clear, nowadays there is controversy about the indication of including the gene in routine clinical genetic testing, due to the lower prevalence or the absence of mutations found in subsequent studies. Here, we present the results of a comprehensive mutational screening of the RAD51C gene in a large series of 785 Spanish breast and/or ovarian cancer families, which, in contrast to the various subsequent studies published to date, includes the functional characterization of suspicious missense variants as reported in the initial study. We have detected 1.3% mutations of RAD51C in breast and ovarian cancer families, while mutations in breast cancer only families seem to be very rare. More than half of the deleterious variants detected were of missense type, which highlights their significance in the gene, and suggest that RAD51C mutations may have been so far partially disregarded and their prevalence underestimated due to the lack of functional complementation assays. Our results provide new evidences, suggesting that the genetic testing of RAD51C should be considered for inclusion into the clinical setting, at least for breast and ovarian cancer families, and encourage re-evaluating its role incorporating functional assays.

SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype.

DNA interstrand crosslink repair requires several classes of proteins, including structure-specific endonucleases and Fanconi anemia proteins. SLX4, which coordinates three separate endonucleases, was recently recognized as an important regulator of DNA repair. Here we report the first human individuals found to have biallelic mutations in SLX4. These individuals, who were previously diagnosed as having Fanconi anemia, add SLX4 as an essential component to the FA-BRCA genome maintenance pathway.

Hepatoblastoma in a 4-year-old girl with Fanconi anaemia.

CASE REPORT: Hepatoblastoma was diagnosed in a 4-year-old girl receiving growth hormone substitution therapy for short stature. Owing to multiple congenital malformations, VACTERL-H (vertebral, anal, cardiac, tracheal, renal and limb anomalies with hydrocephalus) association had been suggested. Elevated chromosomal breakage rates and G2 phase arrest induced by DNA-crosslinking agents in cellular assays confirmed the diagnosis of Fanconi anaemia (FA), a tumour susceptibility syndrome known to be associated with hepatocellular carcinoma following androgen therapy. Subsequent genotyping revealed biallelic mutations in the FANCD1/BRCA2 gene. CONCLUSION: We describe the first case of hepatoblastoma in a patient with FA to raise awareness of this tumour type in the close clinical observation of early cancer-prone forms of this condition, particularly in the presence of FANCD1/BRCA2 mutations. The present case also underscores the importance of FA testing in patients with VACTERL(-H).